Macromolecular polyamine iodine-containing compound, process for its preparation and its use as a contrast agent

Abstract

Biological or synthetic macromolecular polyamine compound. optionally of the dendrimer type, characterized in that it carries at least three radio-opaque iodine-containing derivatives.

We claim: 
     
       1. A mono-dispersed dendrimer-type macromolecular polyamine iodine-containing compound of the formula:   P-- NK.sub.x --A--G!.sub.n                                 (I)     wherein   --P represents a macromolecular radical of said macromolecular polyamine compound,   --N represents a nitrogen atom of said polyamine compound,   --K is selected from the group consisting of a hydrogen atom, lower linear or branched alkyl group, lower linear or branched hydroxy- or polyhydroxy-alkyl group, lower linear or branched alkoxyalkyl group, lower linear or branched alkoxyhydroxy- or alkoxypolyhydroxyalkyl group, and group --A--G,   --x is an integer equal to 0 or 1,   --G is an iodine-containing radio-opaque benzenic derivative of the formula: ##STR44## wherein the substituents R 1  and R 5 , which are identical or different from one another, represent: --iodine   --hydrogen,   --COOH,   --COO -  M y+ , M representing a physiological acceptable cation and y an integer from 1 to 3, ##STR45## which are identical or different from one another, are selected from the group consisting of a hydrogen atom, lower linear or branched alkyl group, lower linear or branched hydroxyalkyl group, lower linear or branched polyhydroxyalkyl group, lower linear or branched alkoxyalkyl group, lower linear or branched alkoxyhydroxy-alkyl group, lower linear or branched alkoxypolyhydroxyalkyl group, the substituents R 2 , R 3  and R 4  being defined as R 1  and R 5  or a group ##STR46## wherein --the substituents R 10 , R 11 , R 12 , R 13  and R 14 , which are identical or different from one another, have the same signification as R 1  and R 5 , and     --B represents a single bond or a group   --R 15  --D--R 16  --wherein R 15  and R 16 , which are identical or different, represent the groups: ##STR47## wherein --R 17  and R 18  have the same signification as R 6  and   --D represents a single bond or has the same significations as R 6  except hydrogen,   --A is a bonding group that can join the amine group of the macromolecular polyamine radical with the iodine-containing radio-opaque benzenic derivative of formula (III), and   n is an integer from 3 to 500, with the proviso that at least one of the substituents R 1 , R 2 , R 3 , R 4 , R 5 , R 10 , R 11 , R 12 , R 13  and R 14  represents an iodine atom.     
     
     
       2. A monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, wherein n is an integer from 30 to 200. 
     
     
       3. A monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, wherein the substituents R 6 , R 7 , R 8 , R 9 , R 17  and R 18  are selected from the group consisting of a hydrogen atom and ##STR48## 
     
     
       4. A monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, wherein the bonding group A is selected from the group consisting of: ##STR49## wherein --R 19  is selected from the group consisting of a lower linear or branched alkyl group, lower linear or branched hydroxyalkyl group, lower linear or branched polyhydroxyalkyl group, lower linear or branched alkoxyalkyl group, lower linear or branched alkoxyhydroxyalkyl group, lower linear or branched alkoxypolyhydroxyalkyl group, --R 20  has the same significations as R 6  and   --R 21  represents a single bond or has the same significations as R 19 .   
     
     
       5. A monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, wherein the radio-opaque iodine-containing benzenic derivative is selected from the group consisting of: ##STR50## 
     
     
       6. Process for the preparation of the a monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, comprising the steps of: --selecting the a monodispersed dendrimer-type macromolecular polyamine compound,   --subjecting at least three of the amine groups of the a monodispersed dendrimer-type macromolecular polyamine compound, either: --to an acylation reaction, in a solvent of the group comprising DMAC, DMF and DMSO, in the presence of a mineral or organic base selected from the group consisting of NaOH, triethylamine, and sodium carbonate, with a compound of the formula:   Z.sub.1 --A--G                                             (VI)     wherein G is a defined in claim 1 and Z 1  --A is selected from the group consisting of: ##STR51## wherein R 19 , R 20 , R 21  are as defined in claim 1 and Z 1  represents a chlorine or bromine atom, the hydroxyl groups present being previously protected; or       --to an alkylation reaction, a solvent selected from the group consisting of DMAC, DMF, and DMSO, in the presence of a mineral or organic base selected from the group consisting of NaOH, triethylamine, and sodium carbonate, with a compound of formula:   Z.sub.2 --A--G                                             (VII)     wherein G is as defined in claim 1 and Z 2  --A is selected from the group consisting of: ##STR52## wherein R 19 , R 20  are as defined in claim 1 and Z 2  is selected from the group consisting of chlorine, bromine, iodine, OMs (O-mesyl) group, OTs (O-tosyl) group, epoxyde, the hydroxyl groups present being previously protected;     --subjecting at least part of the residual amine groups of the macromolecular polyamine compound, after deprotection of the hydroxyl groups present, in a solvent selected from the group consisting of DMAC, DMF, and DMSO, in the presence of a mineral or organic base selected from the group consisting of NaOH, triethylamine, and sodium carbonate, to an alkylation reaction with a compound of the formula:   L--Y                                                       (VIII)     wherein Y has the same significations as Z 2  or represents an activated --CO group in the form of an acid halogenide, an anhydride or an ester, and L is selected from the group consisting of a lower linear or branched alkyl group, lower linear or branched hydroxy- or polyhydroxyalkyl group, lower linear or branched alkoxyalkyl group, lower linear or branched alkoxyhydroxy- or alkoxypoly-hydroxyalkyl group, the hydroxyl groups of which have been protected, and     --deprotecting the protected hydroxyl groups of L.   
     
     
       7. Diagnosis composition for X-rays to be used in a human or animal, comprising an effective amount of at least one a monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, together with a pharmaceutically acceptable carrier. 
     
     
       8. A monodispersed dendrimer-type macro-molecular polyamine iodine-containing compound according to claim 1, wherein n is an integer from 10 to 300 and R 2 , R 3  and R 4  have the same signification as R 1  and R 5 . 
     
     
       9. A monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 1, wherein the macromolecular polyamine compound is selected from the group consisting of polyalkylamines, polyethylenimines, polyamido-amines, branched polylysines and arborols. 
     
     
       10. Diagnosis composition for X-rays, to be used in a human or animal, comprising an effective amount of at least one a monodispersed dendrimer-type macromolecular polyamine iodine-containing compound according to claim 9, together with a pharmaceutically acceptable carrier.